Late recurrence of Cushing disease with ubiquitin-specific protease 8 mutation 19 years after initial surgery

Recurrence after successful transsphenoidal surgery (TSS) for Cushing disease (CD), caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, remains a major clinical concern. Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been implicated in corticotroph tumorigenesis and may contribute to recurrence risk. Here, we report a rare case of delayed CD recurrence 19 years after initial surgical remission. A female aged 36 years underwent TSS for CD with typical clinical and biochemical evidence of hypercortisolism. Magnetic resonance imaging showed a 10 mm pituitary adenoma, and histopathology confirmed an ACTH-producing tumor with a low Ki-67 index (<1%). She achieved long-term postoperative remission. At age 55 years, she developed biochemical and radiological findings consistent with recurrence. Inferior petrosal sinus sampling confirmed localization of the ACTH-secreting lesion to the pituitary gland, and repeat surgery was performed. The recurrent tumor demonstrated a high Ki-67 index. Retrospective Sanger sequencing of the initial tumor identified a USP8 c.2159C>G p.(Pro720Arg) mutation, a common variant in CD. This case underscores the potential role of USP8 mutations in long-latency recurrence and highlights the value of genetic profiling. Lifelong endocrine follow-up may be warranted in patients with USP8-mutated CD, even after extended postoperative remission.